Inflammation, Stroke
Conditions
Keywords
exercise, inflammation, motor performance, skeletal muscle, chronic stroke survivors, treadmill exercise
Brief summary
The purpose of this study is to first define whether abnormalities of skeletal muscle are related to the presence of inflammation and to poor motor performance and whether this can be modified by exercise interventions.
Detailed description
Stroke is the leading cause of disability in the United States. Biological changes in hemiparetic skeletal muscle may further propagate the disability. The investigators report gross muscular atrophy and major shift to fast myosin heavy chain (MHC) isoform distribution in hemiparetic thigh that are related to reduced fitness and slow walking speed. The investigators also find elevated inflammatory mediators, tumor necrosis factor (TNF) and nuclear factor kappa beta (NFkB) in the paretic thigh muscle. No prior studies have systematically examined the profile of hemiparetic muscle contractile proteins and their relationship to function and fitness after stroke. Furthermore, the molecular mechanisms underlying hemiparetic skeletal muscle atrophy and contractile protein abnormalities are unknown. The investigators have investigated treadmill aerobic exercise (T-AEX), as a task-oriented training model. This exercise model can reverse the alterations in MHC profile in hemiparetic leg muscles after stroke. This T-AEX program also improves fitness (VO2) levels, leg strength, and ambulatory performance in chronic stroke. Moreover, post hoc analyses our randomized treadmill exercise program show that specific features of the exercise prescription likely influence the nature of exercise-mediated adaptations. Hypothesis: The investigators propose a randomized clinical study to investigate the hypothesis that in chronic stroke patients a 6 month velocity-based progressive T-AEX program is superior to duration-based progressive T-AEX for improving hemiparetic (HP) leg skeletal muscle contractile protein expression and reducing inflammatory markers to improve muscle function, fitness, and ambulation. Specific Aims: 1) Determine whether skeletal muscle MHC isoform expression is altered and inflammatory mediators, TNF and markers of NFkB activation, present in the hemiparetic vastus lateralis muscle, compared the non-paretic leg and matched non-stroke control leg muscles, and related to muscle function, fitness, and gait performance. 2) Determine whether 6 months progressive T-AEX programs can attenuate this abnormal MHC profile and inflammatory mediators to improve muscle structure and function. Methods: At baseline, bilateral vastus lateralis (VL) biopsies are obtained from chronically disabled, stroke participants with hemiparetic gait to examine the HP and non-P thigh skeletal muscles for alterations in MHC isoforms, key muscle contractile protein, and evidence for inflammation (TNFa) and NFkB activation. Participants are randomized to 6 months of progressive velocity-based or duration-based T-AEX training. Repeat VL muscle biopsies are obtained in the HP limb only after exercise interventions to assess whether 6-month exercise rehabilitation can restore MHC profile and attenuate activation of inflammatory pathways. Expression of the specific MHC isoforms, TNF, and NFKB marker expression (mRNA and protein) are investigated in these muscle tissues by real-time real time (RT)- polymerase chain reaction (PCR), Western Blot analysis, and immunohistochemistry. The investigators will explore relationships between T-AEX mediated changes in MHC expression and inflammatory activation in skeletal muscle after stroke to improve muscle strength, muscle performance, fitness and activity levels, activities of daily living (ADL) performance, and gait deficit severity. Anticipated Results and Relevance: The cross-sectional baseline data will provide the first systematic study of a substantial cohort of stroke patients to define the relationship between altered structural and contractile protein expression to both muscle physiology and clinical measures of muscle performance, metabolic fitness, and rehabilitation mobility outcomes. HP VL muscle will be directly compared to the non-paretic (NP) limb muscle within-subjects and to non-stroke reference controls, in order to better understand the scope of skeletal muscle inflammatory and metabolic abnormalities in the stroke population. The intervention results will allow us to determine the specific requirements of treadmill training that are optimal and crucial to produce the exercise-mediated adaptations in hemiparetic skeletal muscle that lead to improved rehabilitation outcomes to reduce the disability of chronic stroke.
Interventions
OTHERVelocity based treadmill training
6 month of progressive treadmill walking with a safety harness and hand rail support to prevent falls. Treadmill speed is gradually progressed to meet the training heart rate goals for moderate aerobic exercise, when hemiparetic gait velocity can no longer be progressed, incline is added to achieve heart rate training goals. Progression is also based on participant's tolerance, abilities and safety.
OTHERDuration based treadmill training
6 month of progressive treadmill walking with a safety harness and hand rail support to prevent falls. Treadmill duration is gradually progressed to meet the endurance goals for low aerobic intensity exercise, gait velocity and incline do not progress. Progression is based on participant's tolerance, abilities and safety.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Chronic stroke (\>6 months after initial stroke) * Age 40-80 * Stable neurologic deficits * Able to walk with an assistive device * Language skills to understand the training program safely
Exclusion criteria
* No anticoagulation or medical conditions that preclude exercise. * No dementias or depression
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiovascular Fitness (VO2 Peak) | Baseline to 6 month | Cardiovascular fitness is measured by collecting the expired gases during a progressive graded treadmill test. |
| Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a | Baseline to 6 month | Skeletal muscle punch biopsies are obtained from the bilateral (paretic and non-paretic) vastus lateralis thigh muscle, at baseline and after 6 month interventions. Homogenized muscle messenger ribonucleic acid (mRNA) for myosin heavy chain isoforms are analyzed by real time polymerase chain reaction as fluorescent units with normalization to an acidic ribosomal protein, a housekeeping gene. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 30 Foot Walk Time (Sec) | baseline to 6 month | Participants are instructed to walk fast as comfortable on a straight pathway on the floor demarcated by cones. They may use their usual canes, walkers, and orthotics while they walk. The walks are timed, the value is the mean of three trials with an interval rest between each trial. |
Countries
United States
Participant flow
Recruitment details
Veterans with chronic hemiparetic stroke (latency \> 6 months) were recruited from the Baltimore VA and University of Maryland Neurology and Primary care clinics, as well as through Institutional Review Board approved flyers and ads.
Pre-assignment details
Reasons for participant exclusion were not meeting eligibility criteria, screen failures (ischemia on stress test or serious lab abnormalities) new medical conditions, study time requirements, return to work, lost to follow-up, lack of transportation.
Participants by arm
| Arm | Count |
|---|---|
| Velocity Based Treadmill Training 6-month treadmill exercise progressed only gait speed and then incline to achieve moderate aerobic exercise heart rate training goal. | 47 |
| Duration Based Treadmill Training 6-month treadmill exercise at self-selected speed progressed only on training duration. | 52 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 17 | 20 |
| Overall Study | Physician Decision | 6 | 4 |
| Overall Study | Withdrawal by Subject | 6 | 12 |
Baseline characteristics
| Characteristic | Velocity Based Treadmill Training | Duration Based Treadmill Training | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 40 Participants | 42 Participants | 82 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 10 Participants | 17 Participants |
| Age, Continuous | 62 years STANDARD_DEVIATION 3 | 64 years STANDARD_DEVIATION 6 | 63 years STANDARD_DEVIATION 3 |
| Race/Ethnicity, Customized Race African American | 28 Participants | 32 Participants | 60 Participants |
| Race/Ethnicity, Customized Race Caucasian | 16 Participants | 19 Participants | 35 Participants |
| Race/Ethnicity, Customized Race Latino | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 47 participants | 52 participants | 99 participants |
| Sex: Female, Male Female | 11 Participants | 14 Participants | 25 Participants |
| Sex: Female, Male Male | 36 Participants | 38 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 52 |
| other Total, other adverse events | 8 / 47 | 9 / 52 |
| serious Total, serious adverse events | 1 / 47 | 2 / 52 |
Outcome results
Primary
Cardiovascular Fitness (VO2 Peak)
Cardiovascular fitness is measured by collecting the expired gases during a progressive graded treadmill test.
Time frame: Baseline to 6 month
Population: Randomized study design with Intent to treat group by time analysis of change in peak cardiovascular fitness levels between the higher-intensity treadmill training group and the lower intensity training group across baseline to 6 months post-exercise time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Velocity Based Treadmill Training | Cardiovascular Fitness (VO2 Peak) | 6 month | 21.3 ml/kg/min | Standard Error 1.6 |
| Velocity Based Treadmill Training | Cardiovascular Fitness (VO2 Peak) | baseline | 15.9 ml/kg/min | Standard Error 1.7 |
| Duration Based Treadmill Training | Cardiovascular Fitness (VO2 Peak) | 6 month | 17.5 ml/kg/min | Standard Error 1.2 |
| Duration Based Treadmill Training | Cardiovascular Fitness (VO2 Peak) | baseline | 16.6 ml/kg/min | Standard Error 1.2 |
Comparison: Power Calculation: It was calculated that 29 subjects should be randomized to 2 groups to achieve a significant time by group interaction for peak fitness for high-velocity or low velocity duration training groups, assuming a power of 90 percent power and alpha = 0.01, two-tailed analyses.~Primary analyses is a group by time analysis of variance in peak fitness levels between the higher-intensity and lower intensity training groups across baseline to 6 months post-exercise time points.p-value: 0.001ANOVA
Primary
Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a
Skeletal muscle punch biopsies are obtained from the bilateral (paretic and non-paretic) vastus lateralis thigh muscle, at baseline and after 6 month interventions. Homogenized muscle messenger ribonucleic acid (mRNA) for myosin heavy chain isoforms are analyzed by real time polymerase chain reaction as fluorescent units with normalization to an acidic ribosomal protein, a housekeeping gene.
Time frame: Baseline to 6 month
Population: The difference muscle and participant number reflects those that participated and completed pre/post biopsies.~Paretic thigh muscle, at baseline and after 6 month interventions, are analyzed for myosin heavy chain proportions. Values were the mean of duplicates run on polymerase chain reaction were normalized to a ribosomal protein mRNA.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Velocity Based Treadmill Training | Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a | Baseline | 3.35 PCR flourescence units | Standard Error 0.87 |
| Velocity Based Treadmill Training | Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a | 6 months | 4.40 PCR flourescence units | Standard Error 0.71 |
| Duration Based Treadmill Training | Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a | Baseline | 3.64 PCR flourescence units | Standard Error 0.74 |
| Duration Based Treadmill Training | Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a | 6 months | 5.44 PCR flourescence units | Standard Error 0.79 |
Comparison: Power Calculation: It was calculated that 22 participants should be randomized to 2 groups to achieve a significant time by group interaction for myosin heavy chain isoforms for high-velocity or low velocity duration training groups, assuming a power of 90 percent power and alpha = 0.01, two-tailed analyses.p-value: 0.11ANOVA
Secondary
30 Foot Walk Time (Sec)
Participants are instructed to walk fast as comfortable on a straight pathway on the floor demarcated by cones. They may use their usual canes, walkers, and orthotics while they walk. The walks are timed, the value is the mean of three trials with an interval rest between each trial.
Time frame: baseline to 6 month
Population: Randomized study design with intent to treat group by time analysis of change in floor walking time between the higher-intensity treadmill training group and the lower intensity training group across baseline to 6 months post-exercise time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Velocity Based Treadmill Training | 30 Foot Walk Time (Sec) | baseline | 15.4 sec | Standard Error 2.1 |
| Velocity Based Treadmill Training | 30 Foot Walk Time (Sec) | 6 month | 13.8 sec | Standard Error 2.1 |
| Duration Based Treadmill Training | 30 Foot Walk Time (Sec) | 6 month | 15.9 sec | Standard Error 1.9 |
| Duration Based Treadmill Training | 30 Foot Walk Time (Sec) | baseline | 17.2 sec | Standard Error 2.2 |
Comparison: Primary analyses is a group by time analysis of variance in 30 foot walk time (sec) between the higher-intensity and lower intensity training groups across baseline to 6 months post-exercise time points.p-value: 0.81ANOVA